title: The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.
abstract: A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Barrett
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: David T
authors.initials: DT
authors.lastname: Dudley
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.forename: James H
authors.initials: JH
authors.lastname: Fergus
authors.forename: Cathlin M
authors.initials: CM
authors.lastname: Flamme
authors.forename: Amy M
authors.initials: AM
authors.lastname: Delaney
authors.forename: Michael
authors.initials: M
authors.lastname: Kaufman
authors.forename: Sophie
authors.initials: S
authors.lastname: LePage
authors.forename: Wilbur R
authors.initials: WR
authors.lastname: Leopold
authors.forename: Sally A
authors.initials: SA
authors.lastname: Przybranowski
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.forename: Keri
authors.initials: K
authors.lastname: Van Becelaere
authors.forename: Annette M
authors.initials: AM
authors.lastname: Doherty
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kennedy
authors.forename: Dan
authors.initials: D
authors.lastname: Marston
authors.forename: W Allen
authors.initials: WA
authors.lastname: Howard
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Smith
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Warmus
authors.forename: Haile
authors.initials: H
authors.lastname: Tecle
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D009368:Neoplasm Transplantation; D012995:Solubility; D062367:ortho-Aminobenzoates / Q000737:chemistry
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D001565:Benzoates; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C506614:mirdametinib; D004159:Diphenylamine; D048728:MAP Kinase Kinase Kinase 1